Summary: These studies were initiated to determine the endogenous function of the CYP2Cs using the human and the mouse as a model. We have found organ-specific expression of the CYP2Cs in extrahepatic organs such as the heart muscle, endothelial cells of blood vessels, lung, kidney, adrenals, aorta, reproductive organs, white blood cells and eyes (optic nerve, rods and cones. Four potentially new CYP2Cs (CYP2C44, CYP2C50, CYP22C51 and CYP2C52p). Metabolism of arachidonic acid by the five CYPs indicated they were regio and stereospecific selective. Mouse CYP2C40 was found in relatively high amounts in colon, cecum, kidney and heart. CYP2C40 metabolizes arachidonic acid (AA) to 16R- and 16S-HETE. This is the first P450 found to produce 16-HETE as a primary product. Intestinal microsomes also produced 16-HETE. 16R-HETE is thought to be important in processes such as renal vasodilation and inhibiting neutrophil aggregation and adhesion. These initial studies indicate very organ specific expression of CYPs which produce very regio and stereospecific prodcuts of arachidonic acid. Therefore the CYP2Cs may have important physiological roles in heart, cecum, colon, endothelial cells, lung, blood vessels and eyes. This year, we identified a new CYP2C, CYP2C44, in murine kidney. CYP2C44 metabolizes arachidonic acid in a regio and stereospecific manner to 11R,12S-HETE. This EET is known to be important in vasodilation. Human CYP2C8 was found in human heart and aorta. Studies were initiated in human eyes and retinal cells. One or more CYP2Cs appear to be present in human retinal cells.